title: Antagonism of betulinic acid on LPS-mediated inhibition of ABCA1 and cholesterol efflux through inhibiting nuclear factor-kappaB signaling pathway and miR-33 expression.
abstract: ATP-binding cassette transporter A1 (ABCA1) is critical in exporting cholesterol from macrophages and plays a protective role in the development of atherosclerosis. The purpose of this study was to investigate the effects of betulinic acid (BA), a pentacyclic triterpenoid, on ABCA1 expression and cholesterol efflux, and to further determine the underlying mechanism. BA promoted ABCA1 expression and cholesterol efflux, decreased cellular cholesterol and cholesterol ester content in LPS-treated macrophages. Furthermore, we found that BA promoted ABCA1 expression via down-regulation of miR-33s. The inhibition of LPS-induced NF-κB activation further decreased miR-33s expression and enhanced ABCA1 expression and cholesterol efflux when compared with BA only treatment. In addition, BA suppressed IκB phosphorylation, p65 phosphorylation and nuclear translocation, and the transcription of NF-κB-dependent related gene. Moreover, BA reduced atherosclerotic lesion size, miR-33s levels and NF-κB activation, and promoted ABCA1 expression in apoE(-/-) mice. Taken together, these results reveal a novel mechanism for the BA-mediated ABCA1 expression, which may provide new insights for developing strategies for modulating vascular inflammation and atherosclerosis.
authors.affiliation: Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan, China ; Department of Histology and Embryology, University of South China, Hengyang, Hunan, China.
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Zhao
authors.forename: Shi-Lin
authors.initials: SL
authors.lastname: Tang
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Lv
authors.forename: Xin-Ping
authors.initials: XP
authors.lastname: Ouyang
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: He
authors.forename: Feng
authors.initials: F
authors.lastname: Yao
authors.forename: Wu-Jun
authors.initials: WJ
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Lu
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Tang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Fu
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Zhang
authors.forename: Kai
authors.initials: K
authors.lastname: Yin
authors.forename: Chao-Ke
authors.initials: CK
authors.lastname: Tang
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014315:Triterpenes / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D008055:Lipids; D008070:Lipopolysaccharides; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D002784:Cholesterol; D000094062:Betulinic Acid